Colorectal tumors progress through a series of well defined clinical and histopathological stages. This progression is accompanied by a series of genetic changes which include inactivation of several tumor suppressor genes. Several studies have suggested that one or more tumor suppressor genes on chromosome 5q2l are important in the early stages of colorectal tumorigenesis. Recently, we have identified two candidate tumor suppressor genes (APC and MCC) from the chromosome 5q2l region. Both the APC and MCC genes were found to be somatically mutated in colorectal cancers. Furthermore, the APC gene was found to be mutated in the germline of several kindreds with either Familial Adenomatous Polyposis (FAP) or Gardner's Syndrome (GS), two inherited diseases which predispose to colon cancer. The studies outlined in this proposal are aimed at extending these results with APC and MCC in the following areas. First, the clinical significance of APC and MCC in colorectal cancer will be determined. This will include the determination of the prevalence of APC and MCC mutations in human colorectal tumors and in the germline of individuals with FAP and GS. Second, the biochemical properties of MCC and APC will be studied. This will include production of antibodies to APC and MCC, characterization of the APC and MCC protein products, and determination of APC and MCC expression in adult and developing tissues. Third, the functional properties of APC and MCC will be studied. This will include determining the effects of inducing expression of normal APC and MCC protein in colorectal tumor cell lines and determining the effects of reducing endogenous APC and MCC expression using anti-sense technology. The combination of the above studies should provide important insights into the role of APC and MCC in colorectal tumorigenesis.